Chronic pain in systemic lupus erythematosus (SLE) significantly impairs the quality of life and productivity of patients due to the lack of potent and safe painkillers. There is a highly unmet need for the development of novel analgesics. Surprisingly, no animal studies had been reported about the mechanisms underlying chronic pain in SLE until our recent study. We found that activation of microglial macrophage colony- stimulating factor-1 (M-CSF1) receptors and over-production of IL-1? in the spinal dorsal horn play a crucial role in the enhancement of spinal excitatory glutamatergic synaptic transmission and generation of chronic pain in a lupus mouse model, MRL lupus prone (MRL/lpr) mice. Our study demonstrated that controlling the spinal neuroinflammation is an effective approach for the treatment of pain in lupus. GPR109A was newly identified in different immune cell types and its activation produces anti-inflammatory effects. Whether and how spinal GPR109A regulates spinal neuroinflammation and the genesis of pathological pain (including chronic pain in SLE) is unknown. Our overarching hypothesis is that activation of the anti-inflammatory receptor GPR109A in spinal microglia attenuates SLE-induced chronic pain and microglial production of pro- inflammatory mediators, in part, through suppressing microglial N-type calcium channel activity. This hypothesis will be tested in 3 specific aims using a well-established mouse model of human SLE, MRL/lpr lupus-prone mice: 1. To test the hypothesis that chronic pain in MRL/lpr mice is reduced by activation of spinal GPR109A; 2. Test the hypothesis that calcium channels are open (activated) in spinal microglia of MRL/lpr mice with chronic pain, and activation of GPR109A suppresses microglial N-type Ca2+ channel activity in MRL/lpr mice with chronic pain; 3. To test the hypothesis that microglial activation and production of pro-inflammatory mediators are regulated by N-type Ca2+ channels and GPR109A. We will apply multidisciplinary cutting edge techniques (including molecular biology, cell culture, genetics, pharmacology, ex-vivo patch-clamp recording, and behavioral assessments) to reach these aims. This study is the first to uncover analgesic effects of the GPR109A activator and its underlying mechanisms. As GPR109A agonists have been in clinical trials for the treatment of dyslipidemia, completion of this project will result in a novel therapeutic use of these drugs, and a faster, cheaper, and less risky development of analgesics, which has high potential for ?fast-track? clinical approval for their use in patients. Given that spinal neuroinflammation is a common feature shared by many chronic pain conditions, the results collected in the study may also provide a base for the use of GRP109A agonists for the treatment of other chronic pain conditions.